SUMMARY OF WORK: Our studies of mammalian DNA polymerase beta have pioneered the use of a coordinated approach of structural studies (x-ray crystallography, NMR, and spectroscopy), biochemical studies, and mammalian genetic studies to understand genomic stability in mammalian cells. This approach has allowed us to establish the cellular role(s) of DNA polymerase beta in mammalian base excision repair. And, the approach has allowed us to establish a solid framework for future studies of individual amino acid residues in this enzyme in such important endpoints as cellular response to genotoxicants, the rate of DNA repair, coordination of DNA repair with cellular checkpoint control and also with apoptosis signalling, coordination of deoxyribose phosphate removal (lyase activity) with DNA synthesis, the fidelity of DNA synthesis, the fidelity of overall DNA base excision repair, and DNA lesion bypass. Rational drug design, targeting one or more of these features will allow us to strategically regulate base excision repair with DNA polymerase beta specific drugs. Such agents will be useful in cancer chemotherapy and in helping us to better understand the role of DNA repair in oncogenesis and other chronic diseases. Detailed structure-function relationship studies of other base excision repair (BER) enzymes, such as FEN-1, PARP-1, XRCC1, DNA ligases I and III, AP endonuclease, and the various DNA glycosylases, will be undertaken in the future. Development of specific inhibitors or other modulators for these enzymes will allow us to strategically deregulate base excision repair in cells. This will have implications for chemotherapy and for understanding the role of DNA repair in preventing disease after exposure to environmental toxicants.